Abstract
Mapping the connection between genotype and phenotype is an old and important problem in biology and medicine. This challenge has been renewed with efforts to define personalized and precision genomic studies of complex phenotypes. We are using the Drosophila model to dissect the complex genetic interactions between the mitochondrial and nuclear genomes that affect fitness, aging and disease traits, with a focus on mitonuclear coevolution, epistasis and genotype by environment interactions (GxG and GxE, respectively). We have built a panel of mitonuclear genotypes by crossing distinct mtDNA genotypes from D. melanogaster and D. simulans into fully sequenced nuclear genomic strains of the Drosophila Genetic Reference Panel (DGRP). These genotypes show pervasive mitonuclear epistasis for development time, starvation resistance and longevity, each of which is modified by different carbohydrate/protein diets.
Transcriptional profiles of selected mitonuclear genotype pairs further show that each genotype and sex has a private transcriptional response to environmental stressors (diets or hypoxia). Computational analyses of these profiles implicate mtDNA-mediated modification of key transcriptional regulators that are in turn unique to specific nuclear genetic backgrounds. Additional studies of respiration and metabolite profiles with rapamycin treatment implicate mitonuclear interactions in TOR signaling. These data point to the complexity of personalized genomic medicine, but reveal that mitochondrial modifiers of GxG and GxE interactions are phenotypes with their own genetic bases, and not merely complicating factors obscuring the genotype-phenotype map. Forward genetic mapping is underway to identify the specific loci responsible for these effects.